Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the ...advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.
Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities ...have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo.
Transparent implantable devices have received significant attention in neuroscience and biomedical engineering by combining neural recording and optical modalities. Opaque, metal‐based electrode ...arrays for electrophysiology block optical imaging and cause photoelectric artifacts, making them difficult to integrate with optogenetics. Here, a photoelectric artifact‐free, highly conductive, and transparent poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) electrode array is introduced as promising neural implants. The technology which is developed in this work provides transparent neural interfaces through low‐cost, ultra‐facile method compared with other transparent materials being applied to implantable tools. The device exhibits superior optical, mechanical, and electrical characteristics to other studies, thanks to a simple ethylene glycol immersing process. The device performance is highlighted by comparing its light stimulation efficiency and photoelectric artifact extent with conventional thin gold electrodes both in vitro and in vivo. This platform can assemble transparent neural interfaces much more efficiently than any other material candidates and thus has many potential applications.
Ultra‐low cost, facile fabrication of transparent microelectrodes for neural recording is introduced. The electrode array comprises poly(3,4‐ethylenedioxythiophene):poly(stryrenesulfonate) (PEDOT:PSS) ethylene glycol (EG) post treatment, which guarantees high electrical conductivity and high optical transparency. Simultaneous electrophysiology and optogenetics shows a capability of photoelectric artifact‐free neural implants with cost‐effective, simple fabrication process than that of other transparent neural interfaces.
Implantable neural probes are a crucial part of brain–machine interfaces that serve as direct interacting routes between neural tissues and machines. The neural probes require both mechanical and ...electrical properties to acquire high‐quality signals from individual neurons with minimal tissue damage. However, overcoming the trade‐off between flexibility and electrical property is still challenging. Herein, a fiber neural probe, composed of core polymer and Au nanoparticles (AuNPs) on the outer shell, is fabricated by absorbing Au precursor following in situ chemical reduction with a variation of percolating and leaching time. The proposed fiber exhibits excellent electrical properties, with an electrical conductivity of 7.68 × 104 S m−1 and an impedance of 2.88 × 103 Ω at 1 kHz, as well as a Young's modulus of 170 kPa, which is comparable to that of brain tissue (≈100 kPa). Additionally, the AuNPs fiber neural probe demonstrates extremely stable in vivo electrophysiological signal recordings for four months with reduced foreign body responses at the tissue–probe interface. Furthermore, this innovative approach encourages a new paradigm of long‐term recording in the fields of neuroscience and engineering to better understand brain circuits, develop bioelectronic devices, and treat chronic disorders.
A highly conductive, flexible, and biocompatible Au nanoparticles (AuNPs) embedded fiber electrode is developed with balanced electrical and mechanical properties. Compared to a conventional rigid probe, the AuNPs fiber probe can display high signal amplitude and low noise level. The fiber neural probe successfully records neural signals for four months in vivo with negligible immune responses.
Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain‐computer interface. However, the long‐term functionality of these devices is ...hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO‐B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long‐term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO‐B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long‐term functionality of neural devices.
Main Points
KDS2010, a reversible MAO‐B inhibitor, prevent glial scar formation and astrogliosis around implanted neural device.
KDS2010 allows long‐term recordings of neural signals with implantable devices.
Low-intensity, low-frequency ultrasound (LILFU) is the next-generation, non-invasive brain stimulation technology for treating various neurological and psychiatric disorders. However, the underlying ...cellular and molecular mechanism of LILFU-induced neuromodulation has remained unknown. Here, we report that LILFU-induced neuromodulation is initiated by opening of TRPA1 channels in astrocytes. The Ca2+ entry through TRPA1 causes a release of gliotransmitters including glutamate through Best1 channels in astrocytes. The released glutamate activates NMDA receptors in neighboring neurons to elicit action potential firing. Our results reveal an unprecedented mechanism of LILFU-induced neuromodulation, involving TRPA1 as a unique sensor for LILFU and glutamate-releasing Best1 as a mediator of glia-neuron interaction. These discoveries should prove to be useful for optimization of human brain stimulation and ultrasonogenetic manipulations of TRPA1.
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•Ultrasound-induced neuromodulation is initiated by opening of TRPA1 in astrocytes•The Ca2+ entry through TRPA1 causes a release of glutamate through Best1 channels•The released glutamate activates NMDA receptors in neighboring neurons
Oh et al. show that TRPA1 is the molecular sensor and transducer for low-intensity, low-frequency ultrasound (LILFU). With TRPA1’s unique co-localization and cooperation with the glutamate-releasing Ca2+-activated Best1 at the microdomains of astrocytes, LILFU is capable of eliciting neuromodulation as a consequence of neuronal NMDAR activation.
Simultaneous monitoring of electrophysiology and magnetic resonance imaging (MRI) could guide the innovative diagnosis and treatment of various neurodegenerative diseases that are previously ...impossible. However, this technique is difficult because the existing metal‐based implantable neural interface for electrophysiology is not free from signal distortions from its intrinsic magnetic susceptibility while performing an MRI of the implanted area of the neural interface. Moreover, brain tissue heating from neural implants generated by the radiofrequency field from MRI poses potential hazards for patients. Previous studies with soft polymer‐based electrode arrays provide relatively suitable MRI compatibility but does not guarantee high‐resolution electrophysiological signal acquisition and stimulation performance. Here, MRI compatible, optically transparent flexible implantable device capable of electrophysiological multichannel mapping and electrical stimulation is introduced. Using the device, neuropathic pain (NP) relief with a 30‐channel electrophysiological mapping of the somatosensory area before and after motor cortex stimulation (MCS) in allodynia rats after noxious stimulation is confirmed. Additionally, artifact‐free manganese‐enhanced MRI of dramatic relief of pain‐related region activity by MCS is demonstrated. Furthermore, artifact‐free optogenetics with transgenic mice is also investigated by recording light‐evoked potentials. These results suggest a promising neuro‐prosthetic for analyzing and modulating spatiotemporal neurodynamic without MRI or optical modality resolution constraints.
Integration of electrophysiology with magnetic resonance imaging (MRI) is achieved by MRI compatible, transparent Poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) neural implantable device. The neuropathic pain alleviation is demonstrated by this MRI compatible electrode array, simultaneously recording/stimulating the brain with manganese‐enhanced MRI. This work highlights a future technology that eliminates the potential risks and inconveniences of medical imaging of patients with conventional neural implants.
Abstract
NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains ...unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition.
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mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical
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Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing.
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Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in
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mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.
Abstract
Assessing the neurological and behavioral effects of drugs is important in developing pharmacological treatments, as well as understanding the mechanisms associated with neurological ...disorders. Herein, we present a miniaturized, wireless neural probe system with the capability of delivering drugs for the real-time investigation of the effects of the drugs on both behavioral and neural activities in socially interacting mice. We demonstrate wireless drug delivery and simultaneous monitoring of the resulting neural, behavioral changes, as well as the dose-dependent and repeatable responses to drugs. Furthermore, in pairs of mice, we use a food competition assay in which social interaction was modulated by the delivery of the drug, and the resulting changes in their neural activities are analyzed. During modulated food competition by drug injection, we observe changes in neural activity in mPFC region of a participating mouse over time. Our system may provide new opportunities for the development of studying the effects of drugs on behaviour and neural activity.
Brain‐machine interfaces (BMIs) that link the brain to a machine are promising for the treatment of neurological disorders through the bi‐directional translation of neural information over extended ...periods. However, the longevity of such implanted devices remains limited by the deterioration of their signal sensitivity over time due to acute inflammation from insertion trauma and chronic inflammation caused by the foreign body reaction. To address this challenge, a lubricated surface is fabricated to minimize friction during insertion and avoid immunogenicity during neural signal recording. Reduced friction force leads to 86% less impulse on the brain tissue, and thus immediately increases the number of measured signal electrodes by 102% upon insertion. Furthermore, the signal measurable period increases from 8 to 16 weeks due to the prevention of gliosis. By significantly reducing insertion damage and the foreign body reaction, the lubricated immune‐stealthy probe surface (LIPS) can maximize the longevity of implantable BMIs.
Signal sensitivity of neural probes deteriorates over time due to acute and chronic inflammations. To overcome these problems, lubricated immune‐stealth probe surface (LIPS) is fabricated with nonimmunogenic properties. Near‐frictionless properties of LIPS minimizing insertion trauma increases signal‐to‐noise ratio and the number of neurons from short‐term neural recording. Furthermore, anti‐biofouling properties of LIPS improve its longevity, doubling the signal recording time‐length.
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